Ca 2+ sensitisation of force production by noradrenaline in femoral conductance and resistance arteries from rats with postinfarction congestive heart failure Simon Trautner a,b , Ole Amtorp a,e , Soren Boesgaard a , Claus B. Andersen c , Henrik Galbo d , Stig Haunsoe a , Majid Sheykhzade b, * a Department of Cardiology, The Danish National Hospital (Rigshospitalet), Blegdamsvej 9, Copenhagen, DK-2100, Denmark b Department of Pharmacology and Pharmacotherapy, The Danish University of Pharmaceutical Sciences, Denmark c Department of Clinical Pathology, The Danish National Hospital (Rigshospitalet), Blegdamsvej 9, Copenhagen, DK-2100, Denmark d Copenhagen Muscle Research Centre, Bispebjerg Hospital, Copenhagen, Bispebjerg Bakke 23, DK-2400, Denmark e Department of Pharmacology, The Panum Institute, University of Copenhagen, Blegdamsvej 3, DK-2200, Denmark Received 9 July 2005; received in revised form 12 October 2005; accepted 3 November 2005 Abstract In this study we tested the hypothesis that arterial myofilament Ca 2+ sensitivity and/or the Ca 2+ sensitising effect of noradrenaline (NA) is enhanced in post-infarction congestive heart failure (CHF), which could contribute to the high peripheral vascular resistance in this condition. Femoral skeletal muscle resistance and conductance arteries (mean lumen diameters of 159 and 519 Am) from rats with CHF and sham-operated control rats were used. Isometric tension development and intracellular free calcium concentration ([Ca 2+ ] i ) were measured simultaneously in isolated vessel segments using wire myography and the FURA-2 fluorescence technique. In conductance and resistance arteries, the resting levels of [Ca 2+ ] i and tension in physiological saline solution (PSS) and active tension in response to single doses of 125 mM K + (KPSS) were unaffected by CHF. During cumulative application of extracellular Ca 2+ to arteries depolarised with 125 mM K + or activated with 30 AM NA, [Ca 2+ ] i and vessel wall tension were similar in CHF and control rats. However, the conductance arteries showed significantly higher calcium sensitivity than resistance arteries in these experiments. We conclude that an abnormality in the sensitivity of the contractile apparatus to Ca 2+ , or in NA-induced Ca 2+ sensitisation in arterial vascular smooth muscle cells is unlikely to contribute to the ubiquitously elevated vascular resistance associated with CHF. However, our data demonstrate significant differences in vascular Ca 2+ handling, myofilament Ca 2+ sensitivity and tension development between resistance and conductance arteries, regardless of CHF. D 2005 Elsevier Inc. All rights reserved. Keywords: Intracellular calcium; Calcium sensitisation; FURA-2; Noradrenaline; Skeletal muscle resistance arteries; Congestive heart failure 1. Introduction In congestive heart failure, the depressed cardiac function leads to compensatory activation of neurohumoral systems, including the renin – angiotensin – aldosterone, the arginine – vasopressin and the sympathetic nervous systems (Schrier and Abraham, 1999). This neurohumoral activation leads to renal sodium and water retention, reduced compliance of the conductance arteries (Mitchell et al., 2001) and increased skeletal muscle and total peripheral vascular resistance (Sorensen et al., 1999; Sullivan et al., 1989). The reduced compliance of the conductance arteries and the augmented peripheral resistance increase the pulsatile and non-pulsatile afterload on the failing left ventricle, making these effects important targets in the treatment regimens of heart failure (Schrier and Abraham, 1999; Mitchell et al., 2001). The focus of the present investigation is to study potential alterations in arterial structure and function, which may be involved in the deleterious haemodynamic changes in CHF. Systemic factors and local mechanisms importantly con- tribute to set arterial tone. Arteries respond to an increase in 1537-1891/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.vph.2005.11.001 * Corresponding author. Department of Pharmacology, The Danish Univer- sity of Pharmaceutical Sciences, Universitetsparken 2, DK-2100, Copenhagen, Denmark. Tel.: +45 35 30 65 46; fax: +45 35 30 60 20. E-mail address: mash@dfuni.dk (M. Sheykhzade). Vascular Pharmacology 44 (2006) 156 – 165 www.elsevier.com/locate/vph